1. Field of the Invention
The present invention relates to an arginine silicate inositol complex and its use in the prevention and treatment of a variety of disease states and disorders.
2. Description of the Related Art
Until recently, infectious disease had been the greatest threat to public health and welfare in the United States and other developed societies. However, the advent of modern vaccines and antibiotics, along with increasing longevity, changing dietary habits, and a lack of physical activity, have raised the importance of degenerative disorders as a threat to health. Examples of such chronic diseases include osteoporosis, arthritis, type II diabetes, and cardiovascular disease. A common factor in the development of many of these disorders is “metabolic syndrome” or “syndrome X”, which is characterized by increased glucose intolerance and insulin resistance and results in hyperinsulinemia, obesity, dyslipidemia, hypertension, disturbances in hormone function and immune function, and atherosclerosis.
Measures to prevent and oftentimes to treat these disorders usually begin with lifestyle and dietary changes. However, these interventions meet with a varying degree of success, due in part to the rigid requirements of some prescribed regimens. In light of this, as well as the increasing incidence of obesity in all age groups, there is great interest in pharmaceutical and nutraceutical research to find drugs and supplements to prevent and treat these disorders.
An example of such a disorder is atherosclerosis, which is a complex and chronic disease involving the gradual accumulation of lipids, collagen, elastic fibers and proteoglycans in the arterial wall. Current methods of managing atherosclerosis include a low-fat diet, exercise and various cholesterol-lowering drugs. Although these methods can significantly retard the progression of atherosclerosis, they are not entirely satisfactory.
Heparin sulfate proteoglycans (HSPGs) produced by vascular endothelium are believed to retard the migration, multiplication and phenotypic transition of vascular smooth muscle cells, events which play a central role in the atherogenic process, and to maintain an anticoagulant luminal surface by binding and activating antithrombin III (Clowes et al., Nature, 265:625-626, 1977; Guyton et al., Circ. Res., 46:625-634, 1980; Edelman et al., Proc. Natl. Acad. Sci. U.S.A., 87:3773-3777, 1990).
Various silicon compounds administered orally or parenterally have been demonstrated to inhibit cholesterol-induced intimal hyperplasia (atherosclerosis) in rabbits (Loeper et al., Athersclerosis, 33:397-408, 1979; Loeper et al., in Biochemistry of Silicon and Related Problems, Plenum Press, New York, 1978, pp. 281-296; Garson et al., J. Pharm. Sci., 60:1113-1127, 1971). The injection or ingestion of nutritionally available silicon compounds (i.e. monomethyltrisilanol, lysine silicate, sodium silicate) prevented the characteristic intimal thickening and fragmentation of arterial elastic fibers observed in atherosclerosis. Additionally, several epidemiological studies report that increased dietary intakes of silicon are associated with a reduced risk of coronary heart disease in humans (Schwarz et al., Lancet, i:454-457, 1977; Schwarz et al., Lancet, i:538-539, 1977; Bassler, Brit. Med. J., 1:919, 1978; Parr, Lancet, i:1087, 1980).
Evidence suggests that silicon intake can also affect bone and joint health. Studies in growing young rats and chicks show that severe dietary silicon deficiency results in abnormal bone and joint structures, apparently due to subnormal production of collagen and mucopolysaccharides (Carlisle, J. Nutr. 106:478-484, 1976; Carlisle, J. Nutr. 110:1046-1055, 1980). Silicon promotes the synthesis of collagen and mucopolysaccharides in vitro (Carlisle et al., Fed. Proc. 37:404, 1978; Carlisle et al., Fed. Proc. 39:787, 1980). The biochemical method by which silicon achieves this effect are unknown. Silicone has been shown to enhance bone mineral density. When an organosilicon compound (monomethyltrisilanol) was administered to postmenopausal women by injection at a dose of 50 mg twice weekly, femoral density increased significantly by an average of 4.7% over 14 months of administration (Eisinger et al., Magnesium Res. 6:247-249, 1993). In ovariectomized rats, oral orthosilicic acid slowed bone turnover and increased the bone formation rate (Hott et al., Calcif. Tissue Int. 53:174-179, 1993).
Bone and cartilage are dynamic tissues in both juvenile and adult animals. In bone, osteoclasts solubilize the hydroxyapatite bone matrix and degrade collagen, whereas osteoblasts concurrently rebuild bone through collagen synthesis and hydroxyapatite deposition. Analogously, chondrocytes in cartilage simultaneously degrade the collagen and proteoglycan matrix and resynthesize it. The impact of silicone on bone and cartilage formation in adult animal is essentially unknown. However, it is highly unlikely that the role of silicon in bone and cartilage metabolism is limited to juvenile animals.
The nutritional role of silicon is to support adequate synthesis of mucopolysaccharides, proteoglycans and collagen (Schwarz et al., Nature, 239:333-334, 1972; Carlisle, Science, 178:619-621, 1972; Carlisle, J. Nutr., 106:478-484, 1976; Schwarz, in Biochemistry of Silicon and Related Problems, Plenum Press, New York, 1978, pp. 207-230). Optimal silicon nutrition may promote production of protective HSPGs by endothelial cells.
Arginine, an essential amino acid, is the biosynthetic precursor for the nitric oxide (NO) produced by vascular endothelium (Moncada, New Engl. J. Med., 329:2002-2012, 1993). NO exerts vasodilatory, antiatherosclerotic, antithrombotic and antioxidant effects, and deficient endothelial production of NO may play a prominent pathogenic role in atherosclerosis, hypertension and diabetes (Calver et al., J. Hypertension, 10:1025-1031, 1992; Cooke et al., Arterioscler. Thromb., 14:653-655, 1994; Rubanyi, in: Cardiovascular Significance of Endothelium-Derived Vasoactive Factors, Futura Publishing Co, Inc., New York, 1991, pp. xi-xix; Bonnefont-Rousselot, Curr. Opin. Clin. Nutr. Metab. Care, 5:561-568, 2002; McPherson et al., Biochem. Biophys. Res. Comm., 296:413, 2002). In some though not all clinical studies, parenteral or oral administration of arginine has enhanced vascular NO synthesis (Drexler et al., Lancet, 338:1546-1550, 1991). In animal models of hypertension, arginine supplementation has moderated the increase in blood pressure (Chen et al., J. Clin. Invest., 88:1559-1567, 1991; Laurant et al., Clin. Exp. Hyperten., 17:1009-1024, 1995). Thus, under at least some circumstances, arginine availability can be rate-limiting for NO production. A recently published clinical study indicates that oral arginine can enhance endothelium-dependent relaxation in hypercholesterolemic young people (Creager et al., J. Clin. Invest., 90:1248-1253, 1992; Clarkson et al., J. Clin. Invest., 97:1989-1994, 1996) which is indicative of increased efficiency of vascular NO production.
Also related to metabolic syndrome is a condition affecting women called Polycystic Ovary Syndrome (PCOS) or Stein-Leventhal Syndrome. This syndrome affects an estimated 5% to 10% of women. The condition is characterized by 1) irregular or absent menses, 2) numerous cysts on the ovaries, 3) high blood pressure, 4) acne, 5) elevated insulin levels, insulin resistance, or type II diabetes, 6) infertility, 7) excess hair on the face or body, 8) male-pattern baldness, 9) abdominal obesity, and 10) abnormal lipid profiles.
The hallmark features of PCOS are obesity, insulin resistance, abnormal lipid profile, excessive hair growth, anovulation, and infertility. Studies with insulin sensitizers (“glitazones”) have demonstrated some beneficial effects on this patient population with respect to these characteristics. Recently, the safety of glitazones has been challenged given the increased frequency of liver toxicity.
There is a constant need for therapeutic/prophylactic agents capable of preventing or retarding the progression of cardiovascular diseases and disorders, promoting the formation of bone and cartilage, and preventing and treating diseases and disorders related to metabolic syndrome, including diabetes. The present invention addresses these needs.